The principal objective of this research is to determine the role of the heart in the development of resistance to shock. The mechanisms of this resistance are not known. The goals of these studies are to establish some of the mechanisms by correlating alterations in morphology and biochemistry of the myocardium and coronary arteries with hemodynamic and physiologic parameters in dogs made resistant to a usually lethal degree of hemorrhagic hypotension. Preliminary studies have shown that 2 episodes of 1 hour of hemorrhage (36 mmHg) is sufficient to produce resistance (100% survival) in dogs subjected to 2 hours of shock. Therefore, resistance will be induced by either a sublethal (1 hour at 36 mmHg) hemorrhage administered 2 times at 3-week intervals, or 5 days of injections of increasing concentrations of norepinephrine. Each group of pretreated dogs will then be subjected to 4 hours of hypovolemic hypotension at 36 mmHg using a modification of the Wiggers hemorrhagic shock model. Control groups will be run in parallel. At each 3-week bleeding episode and during the terminal 4-hour shock studies, measurements will be made every 10 minutes of heart rate, respiratory rate, body temperature, blood pressure, shed blood volume and, at preshock and 1 hour intervals, blood pO2, PCO2, pH, hematocrit, oxygen content, lactic acid, catecholamine and prostacyclin levels will be determined. In addition, at the time of the terminal 4-hour shock study, myocardial blood flow will be measured in a subgroup of 5 dogs from each of the resistant groups. After the terminal study, dogs that die or those that survive 24 hours and are sacrificed will be autopsied. Gross specimen, light and electron microscopic examinations will be performed, noting the amount of subendocardial hemorrhage, contraction band and zonal lesion formation, and necrosis in the myocardium and coronary arteries. The catecholamine content of the myocardium as well as prostacyclin synthesizing capability of the coronary arteries wiol be measured. The relationships between prostacyclin synthesis by the coronary arteries, prostacyclin blood levels and their effects on catecholamines levels in the myocardium and blood in resistant and non-resistant animals will be elucidated. Hemodynamic and physiologic responses to these biochemical alterations will be correlated with the degree of morphologic change in the heart. These studies are of importance because they will contribute to our understanding of the development of shock resistance and give direction to future studies on the development of therapeutic interventions that protect the heart during shock.